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Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach mainly for the treatment of pain. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. As a result of a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, compound 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, compound 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 = 367±24 nM). Molecular modelling studies using a homology model of a single TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing two different binding modes for the agonist and the antagonist.

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Purpose: There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. Methods: Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. Results: Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen–Roscoe law of reciprocity and the Lambert–Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. Conclusions: Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.

Kv7 K+ channels represent attractive pharmacological targets for the treatment of different neurological disorders, including epilepsy. In this paper, 42 conformationally restricted analogues of the prototypical Kv7 activator retigabine have been synthesized and tested by electrophysiological patch-clamp experiments as Kv7 agonists. When compared to retigabine (0.93 ± 0.43 μM), the EC50s for Kv7.2 current enhancements by compound 23a (0.08 ± 0.04 μM) were lower, whereas no change in potency was observed for 24a (0.63 ± 0.07 μM). In addition, compared to retigabine, 23a and 24a showed also higher potency in activating heteromeric Kv7.2/Kv7.3 and homomeric Kv7.4 channels. Molecular modeling studies provided new insights into the chemical features required for optimal interaction at the binding site. Stability studies evidenced improved chemical stability of 23a and 24a in comparison with retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric scaffold for the design of chemically stable, highly potent and selective Kv7 agonists.